17-alkylsulfonyl and 17-alkylsulfinyl substitution products of 4-androsten-3-one



United States Patent 17-ALKYLSULFONYL AND 17-ALKYLSULFINYL gIBgEITU'HON PRODUCTS 0F 4-ANDROSTEN- Raymond M. Dodson, Park Ridge, and Paul B. Sollman, Skokie, 11]., assignors to G. D. Searle & Co., Chicago, 11]., a corporation of Illinois No Drawing. Application October 25, 1955, Serial No. 542,786

8 Claims. (Cl. 260397.3)

The present invention relates to a new class of thiosteroids, and is specifically concerned with l7-alkylsulfonyl and 17-alkylsulfinyl substitution products of 4- androsten-3-one. The compounds of the present invention can be represented by the structural formula ower) alkyl the l7oc-8lkYlSlllfOI1Yl compounds having the structural formula B. 0==0 CH3! and the 17B-alkylsulfony1 compounds having the structural formula 2,806,041 Patented Sept. 10, 19 51 ice The sulfoxides of this invention include stereoisonieric 17a-alkylsulfinyl compounds having the formulas R i=0 CH:

and

O= on,

in which the opposite configurations of the sulfoxide oxygen are represented by arbitrary means, and stereoisomeric 17 ,B-alkylsulfinyl compounds having the formulas R i=0 CH3 and in which the opposite configurations of the sulfoxide oxygen are similarly represented by arbitrary means. The term R in the foregoing structural formulas represents a lower alkyl group.

It is further to be noted that for purposes of convenience, the sulfones and sulfoxides are represented herein by their classical covalent bond structures, whereas the modern view, less easily representable, is that these compounds are resonance hybrids of the covalent and semipolar double bond structures. It will be obvious that lack of agreement among those skilled in the art as to the precise nature of the valence bonds in sulfones and sulfoxides does not in any way limit the useful applications of the compounds of this invention. 7

Among the starting materials suitable for the manufacture of the compounds of this invention are the 17- alkylthio substitution products of 5-androsten-3fl-ol and derivatives thereof described in our copending application, Serial No. 485,606, filed February 1, 1955, now

v Q a U. S. Patent 2,753,361' and the l7-alkylthio substitution products of 4-androsten-3-one described in our copending application, Serial No. 491,507, filed March 1, 1955, now U. S. Patent2,763,669. a

In one of the methods suitable for the manufacture of the 'compounds of this invention, a' 17-alkylthio-5- androsten-3/3-ol is oxidized to the corresponding sulfoxide or sulfone by treatment with a peroxy acid, such as perbenzoic acid. Other peroxidic reagents, including performic acid, peracetic acid,.and perphthalic acid, are suitable for use in carrying out this oxidation. The resulting l7-alkylsulfonyl or l7-alkylsulfinyl substitution product of -androsten-3fi-ol is then oxidized with a reagent such as aluminum isopropoxide in toluene and cyclohexanone, whereby there is obtained the l7-alkylsulfonyl or 17- alkylsulfinyl substitution productv of 4.-androsten-3-one.

In an alternate method for the manufacture of the compounds of this invention, a l7-alkylthio-4-androsten 3-one is oxidized with a peroxy acid such as perbenzoic acid, whereby a l7-alkylsulfonyl or l7-alkylsulfinyl substitution product of 4 androsten-3-one is formed.

In applying the oxidative procedures of our invention, we have found that the. sulfur atom of the l7-alkylthio substitution product of 5-androsten-3B-ol or of 4-androsten-3-one is so rapidly oxidized by peroxy acids such as perbenzoic acid, that sulfoxides and sulfones can be prepared in good yield and in a high state of purity Without the necessity of protecting the 3-hydroxy or 3-oxo group, or the neighboring double bond, from oxidative attack. For example, treatment of a. solution of a 1'7-alkylthio-5 androsten-3fi-ol with approximately one molecular equivalent of perbenzoic acid yields predominantly a mixture of stereoisomeric sulfoxides, both of which retain the configuration of carbon atom number 17 of the original thioether. Only small amounts of a sulfone and unreacted starting material are isolated when the oxidation reaction is run in thismanner. When a solution of a l7-alkyl-thio-5-androsten-3B-ol is treated with approximately two molecular equivalents of perbenzoic acid, the principal product obtained is the sulfone, which retains the configuration at carbon atom number 17 of the original thioether. These sulfoxides and sulfones are converted to the compounds of the present invention by treatment with an oxidizing medium which converts the 5-en-3-ol grouping to a 4-en-3-one.

The claimed sulfoxides and sulfones are also obtained by treating a 17-alkylthio-4-androsten-3-one With, respectively, approximately one molecular equivalent or approximately two molecular equivalents of a peroxy acid such as perbenzoic acidi The sulfones of this invention can also be prepared by oxidation of the corresponding stereoisomeric sulfoxide mixture with one molecular equivalent of a peroxy acid. For other purposes, separation of the stereoisomeric sulfoxide mixture into its individual components is desired, and this result dures' described hereinafter.

.Thecompounds of this invention have valuable physiological properties. They possess some of the usefulactivities of the naturally-occurring adrenocortical hormones. They are, for example, anti-inflammatory agents, as shown by their etfectiveness in reducing inflammation of the iris. They' exhibit other valuable'pharmacological properties which can be regarded as anti-hormonal. Thus, the claimed compositions inhibit the ability of desoxycorticosterone to. cause. sodium retention. The compounds consequently show auseful range ofproperties and in many respects are marked improvements'over the compositions of the prior art. v

w This invention will appear more fully from the'examples which follow. These'examples are set forth byway of illustration only, and it will be understood that the invention is not to be construed as limited ;in spirit or in scope by the detailscontained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in' the art, In these. examples isachieved by proce- 7 4 p temperatures are given in degrees Centigrade C.) and quantities of materials in parts by weight.

Example 1 A stirred solution of-9.6 parts of l7cc-II1EthYl-thl0-5- androsten-3/3-ol in 880 parts of'benzene is treated over a period of 30 minutes by the gradual addition. of a 0.3 molar solution of perbenzoic acid in benzene containing a total of 8.28 parts of perbenzoic acid. After an additional hour the solution is washed with'sodium' bicarbonate solution and with water and then concentrated to pm I O==O CH8 CH3! HO Example 2 tained when the organic. phase is concentrated to dryness is dissolved in benzene, and the crude product is reprecipitated by the addition of petroleum ether. Further purification by recrystallization from aqueous ethanol or from a. mixture of benzene and petroleum ether yields l7u-propylsulfonyl 5 -'androsten-318-ol. This compound has the structural formula 7 Example 3 Five parts of 17a-methylsulfonyl-S-androsten-Elfi-ol is dissolved in a solution" prepared from 3.6 parts of potassium and parts of tert.-butanol. This reaction mixture is heated under reflux for 17 hours and then concentrated by distillation to about two-thirds of its original volume. The remaining solution is poured into about 300 parts of ice Water and this mixture is acidified by the addition of 15 parts of concentrated hydrochloric acid. The precipitate'd product is collected on a filter washed with Water, dried, and recrystallized from ethyl alcohol or from ethyl acetate. In this manner there is obtained the isomerized sulfone, l7B-methy1sulfonyLS-andIoSten-SB-ol melting at 242-244 C. This compound has the structural formula Example 4 A stirred solution of 1.80 parts of 17-,6-butylthio-5- androsten 3B-ol in 350 parts of benzene is treated over a period of 20 minutes by the gradual addition of a 0.3 molar solution of perbenzoic acid in benzene containing a total of 1.40 parts of perbenzoic acid. The reaction mixture is allowed to stand at room temperature for an additional hour, after which it is washed with sodium bicarbonate solution and with water and then concentrated to dryness. Partial purification of the residual product is achieved by redissolving it in benzene and precipitating it by the addition of petroleum ether. Recrystallization from a mixture of benzene and petroleum ether then gives purified 17 3-butylsulfonyl-5-androsten-3fi-ol having the structural formula 0: =0 CH: Cm

Example 5 A solution of aluminum isopropoxide is prepared by stirring 250 parts of this compound with 900 parts of toluene, and by decanting from the small amount of insoluble residue.

A mixture of 13 parts of 17a-methylsulfonyl-5-androsten-35-ol, 305 parts of anhydrous toluene, 50 parts of the previously prepared solution of aluminum isopropoxide in toluene and 95 parts of cyclohexanone is heated under reflux for 30 minutes. It is then mixed with a solution of 100 parts of sodium potassium tartrate in 1000 parts of water and distilled with steam. The crystalline product which separates as the organic solvent is removed is collected on a filter and recrystallized from ethyl acetate. This product is 17ot-methylsulfonyl-4-androsten-3-one. It melts at 215216 C. and has the structural formula 0: 1 =0 CH3 CHs Example 6 It is washed with 5% sodium bicarbonate solution and with several portions of water, after which the organic phase is dried and evaporated. Recrystallization of the residue from aqueous methanol yields a relatively stable hemihydrate of 17u-methylsulfonyl-4-androsten-3-one. The purified anhydrous compound can be obtained by sublimation at 200 C. at a pressure of about 0.05 mm. This preparation melts at 2l5-216 C. and is identical with the product of Example 5.

Example 7 A solution of aluminum isopropoxide is prepared by stirring 250 parts of this compound with 900 parts of toluene, and by decanting from the small amount of insoluble residue.

A mixture of 15.5 parts of l7fl-methylsulfonyl-5-androsten-3 5-01, 870 parts of anhydrous toluene, 70 parts of the solution of aluminum isopropoxide in toluene and 185 parts of cyclohexanone is heated under reflux for 30 minutes. The cooled reaction mixture is treated with a solution of parts of sodium potassium tartrate in 1500 parts of water and distilled with steam. The precipitated product, 17,8methylsulfonyl-4-androsten-3-one, is collected and purified by recrystallization from a mixture of benzene and ether. This compound melts at about 214- 2 l6 C. and has the structural formula A marked depression of the melting point is observed with mixtures of this compound and the isomeric 17a-methylsulfonyl-4-androsten-3-one.

Example 8 By the procedure of Example 7, with the substitution of 17 parts of l7a-propylsulfonyl-5-androsten-3p-ol for the 17,8-methylsulfonyl-5-androsten-3fi-ol, there is obtained 17u-propylsulfonyl-4-androsten-3-one. This compound has the structural formula CsHt l CH: CH:

Example 9 By the procedure of Example 7, with the substitution of 17.5 parts of 17B-butylsulfonyl-5 andosten-35-ol for the 17fl-methylsu1fonyl-5-androsten-3B-ol, there obtained 17l8-butylsulfonyl-4 androsten-3-one. This compound has the structural formula CH8 CH:

' the column with these solvent mixtures.

. p Example 10 V A stirred solution of 6.4 parts of 17a-methylthio-5- androsten 3p-ol in 440 parts of benzene is treatedover a period of 20 minutes by the gradual addition ofja 0.45 molar solution of perbenzoic 'acid'in benzene containing a totalof 2.76' parts of perbenzoic acid. The reaction inixture is allowed to stand at room temperature for an additional hour and is thenextracted with dilute-sodium bicarbonate solution and withsever-al portions of water. A'solid product, insolublein either the organic or aqueous phaselis' present during the extraction procedure, and is collected on a filter.- This product amounts to about 2' parts and is digested with 9 parts of hot benzene.

The fraction which remains undissolved is combined with the fraction which crystallizes when the hot benzene solu- 'tion is cooled, and the combined material is purified by recrystallization from aqueousinethanol. In this manner there is obtained a 'l7a methylsulfinyl-5-androsten-3p-ol having amelting'po'int 015244-245 C. and a specific rotation of 75 in chloroform solution. 7 A stereoisomericfsulfoxide is obtained from the benzene solution remaining after the original extraction of the reaction mixture. The crystalline residue obtained by evaporation of ;this benzene solution, when recrystallized successively from ethyl acetate and from benzene, yields a l7a-methylsulfinyl-5-androsten=3,6-ol melting at 182-184" C. and having a specific rotation of --l67 in chloroform solution. Thesetwo isomeric sulfoxides differ in the spacial orientation of the groups bonded to the sulfur atom, and they have the structural formula wherein the valence bonds directed between the sulfur atom and the oxygen atom, and between the sulfur atom and the methyl group, are without configurational significance.

' Example 11 A stirred solution of 2.68 parts of l7fi-methylthio-5- androsten-3/3-ol in 88 parts of benzene is treated over a period of 20 minutes by the gradual addition of a 0.13 molar solution of perbenzoic acid in benzene containing a total of 1.15 parts of perbenzoic acid. The reaction mixture is then poured on a chromatography column prepared from 155 parts of silica. The column is eluted successively-with 450 parts of a 5 volume percent solufiOD. of ethyl acetate inbcuzene, with 900 parts of a 4,0 volumepercentsolution of 'ethyl acetate in benzene, and;with"900 parts of a 50'volume percent solution of ethyl acetate in benzene. BenzoiQ acid isjremoved item 1800 parts of ethyl acetate then yields a small amount of 17fl-methylsulfonylrfieandrosten-3B-ol. The column is next eluted with 1800 partszof-a 5 volume percent solution of acetone in ethyl acetate and with 9000 parts of a volume percent solution of acetone in ethyl acetate. The crystalline fractions obtained by elution with the first portions of the 110 volume percent solution of acetone in ethyl acetate yield, after recrystallization from acetone and from aqueous methanol, a purified 17,3-methyl- Elution with 1 sulfinyl-5-androsten-3p-ol which 'melts'with decomposition 5 at about 271-273 C. This isomer has a specific rotation of about +7 in chloroform solution. Fractions eluted from the chromatography column with later portions of the 10 volume percent solution of acetone in ethyl acetate give crystalline residues which consist principally of mixtures of the stereoisomeric sulfoxides. Eluates obtained with the final portions of the 10 volume percent solution of acetone in ethyl acetate, as well as later eluates obtained with a 50 volume percent solution of acetone in ethyl acetate and with acetone contain chiefly the other stereoisomeric sulfoxide. The crystalline residue obtained by concentration of these eluates is recrystallized successively from acetone, from aqueous methanol, from ethyl acetate, and from aqueous methanol to yield the stereoisomeric l7,8-methylsulfinyl-5 androsten- 35-01. This compound is obtained as a hemihydrate. It melts withdecomposition at about 283288 C. and has a specific rotation of about .ll5 in chloroform solution. These stereoi-someric sulfoxides have the structural formula Example 12 A stirred solution of 1.59 parts of 17a-methylthio-4- androsten-B-one in 88 parts of benzene is treated over a period of 30 minutes by the addition of a 0.45 molar solution of perbenzoic acid in benzene containing a total of 0.69 part of perbenzoic acid. The reaction mixture is washed with dilute sodium bicarbonate solution and with several portions of water, after which it is concentrated to dryness. A preliminary purification is achieved by recrystallizing the solid residue from a mixture of benzene and petroleum ether containing about equal parts by volume of each solvent component. In this manner there is recovered about 1,2. parts of product melting at about l170 C. and consisting of a mixture of isomers. For some purposes this mixture of isomers is satisfactory for use. vWhenthe individual pure isomers are desired, their separation is achieved in the following manner. The product melting at about C. is partitioned into 4 crystalline crops by recrystallization from aqueous methanol, each crop being obtained by concentration of the mother liquor from the previous crop. The first crop, melting at about 220225 aqueous methanol and finally from ethyl acetate to yield a purified 17a-methylsulfinyl-4 androsten-3-one having a melting point of 233234 C. and a specific rotation of +89.5 in chloroform solution. The remaining three crops, which melt in the range of approximately 160- 170 C., are combinedin ether solution, and the solution prepared in thismanner is evaporated to a viscous oil. Crystallization from petroleum ether and finally from a mixture of ethyl acetate and petroleum ether yields an isomeric a17d-methylsulfinyl-4-androsten-3gone, melting at 167.5-168.5..C. and exhibiting a specific rotation of 3. 3 in chloroform solution. These two isomeric C. is recrystallized again from 9 sulfoxides differ in the spacial orientation of the groups bonded to the sulfur atom, and they have the structural formula wherein the valence bonds directed between the sulfur atom and the oxygen atom, and between the sulfur atom and the methyl group, are without configurational significance.

Example 13 A stirred solution of 7.47 parts of l7fi-methylthi0-4- androsten-3-one in 175 parts of benzene is treated over a period of 35 minutes by the gradual addition of a 0.23 molar solution of perbenzoic acid in benzene containing a total of 3.24 parts of perbenzoic acid. The reaction is slightly exothermic. The benzene solution is then washed with dilute sodium bicarbonate solution and with water, dried, and poured on a chromatography column prepared from 350 parts of silica. The column is eluted successively with benzene, with mixtures of benzene and ethyl acetate containing gradually increasing proportions of ethyl acetate, with ethyl acetate, with mixtures of ethyl acetate and acetone containing gradually increasing proportions of acetone, and with acetone. A small amount (about 0.2 part) of 17B-methylsulfonyl-4-androsten-3-one is eluted from the column with a 40 volume percent solution of ethyl acetate in benzene. One of the stereoisomeric l75-methylsulfinyl-4-androsten-3-ones is eluted from the column with a 90 volume percent solution of ethyl acetate in benzene. Crude crystalline fractions containing predominantly this isomer melt in the range of 145-168" C. Further purification by recrystallization from aqueous methanol afiords the purified isomer of 17B-methylsulfinyl-4-androsten-S-one which melts at about 152-154" C., resolidifies, and melts again at about 170-172 C. This isomer has a specific rotation of approximately +177 .5 in chloroform solution. The next fractions eluted from the chromatography column give crystalline residues which consist principally of mixtures of the stereoisomeric sulfoxides. Following these intermediate fractions, higher melting crystalline fractions are obtained by elution of the column with ethyl acetate and with mixtures of ethyl acetate and acetone. These crude crystalline fractions melt in the range of ISO-218 C. Further purification by recrystallization from a mixture of benzene and petroleum ether affords the other stereoisomeric 175 methylsulfinyl 4 androsten 3 one which melts at about 222223.5 C. and which has a specific rotation of approximately +52.5 in chloroform solution. If desired, the intermediate fractions containing the mixture of stereoisomeric sulfoxides can be separated into their purified isomeric components by fractional crystallization. Recrystallization of the mixture from aqueous methanol afiords crystalline crops which after additional crystallizations yield the isomer melting at 170172 C. The residues obtained from the crystallization liquors of this isomer, after repeated recrystallization from mixtures of benzene and petroleum ether, afiord the isomer melting at 222223.5 C. These two isomeric sulfoxides difier in the spacial orientation of the groups bonded to the sulfur atom, and they have the structural formula wherein the valence bonds directed between the sulfur atom and the oxygen atom, and between the sulfur atom and the methyl group, are without configurational significance.

Example 14 A stirred solution of 7.2 parts of 17fi-butylthio-5-androsten-SB-ol in 880 parts of benzene is treated over a period of 20 minutes by the gradual addition of a 0.45 molar solution of perbenzoic acid in benzene containing a total of 2.74 parts of perbenzoic acid. The reaction mixture is allowed to stand at room temperature for an additional hour and is then extracted with dilute sodium bicarbonate solution and with several portions of water. Suflicient additional benzene is added to redissolve any organic product which precipitates during these operations. Separation and concentration of the organic phase affords a residue which consists substantially of a mixture of the two stereoisomeric 17/3-butylsulfinyl-5-androsten-3fi-ols.

A solution of aluminum isopropoxide is prepared by stirring 250 parts of this compound with 900 parts of toluene, and by decanting from the small amount of insoluble residue.

A mixture of 12 parts of the stereoisomeric mixture of l7fi-butylsulfinylw5-androsten-3p-ols, 700 parts of anhydrous toluene, 60 parts of the solution of aluminum isopropoxide in toluene and 155 parts of cyclohexanone is heated under reflux for 30 minutes. The cooled reaction mixture is treated with a solution of parts of sodium potassium tartrate in 1500 parts of water and distilled with steam. The precipitated product, which is a stereoisomeric mixture of l7fl butylsulfinyl-4-androsten- 3-ones, is collected and washed. If the purified stereoisomers are desired, they are obtained by pouring a henzene solution of the crude product on a silica gel chromatography column and eluting the column successively with benzene, with mixtures of benzene and ethyl acetate containing gradually increasing proportions of ethyl acetate, with ethyl acetate, with mixtures of ethyl acetate and acetone containing gradually increasing proportions of acetone, and with acetone. The sulfox-ides obtained in this manner have the structural formula wherein the valence bonds directed between the sulfur atom and the oxygen atom, and between the sulfur atom and the hutyl group, are without configurational significance.

Example 15 a A stirred solution of 2.5 parts of 17fl-butylthio-4-androsten-B-one in 260' parts of benzene is treated over a period of 30 minutes by the addition of a 0.45 molar solution of perbenzoic acid in benzene containing a total of 0.96 part of perbenzoic acid, The reaction mixture is washed with dilute sodium bicarbonate solution and with several portions of water, after which it is concentrated to dryness. .In this manner there is obtained a mixture of the two stereoisomeric 17B-buty1sulfinyl-4-androsten-3- ones. The sulfoxides of this mixture are identical with the sulfoxides obtained by the procedure of Example 14.

What is claimed is:

1. A compound of the structural formula '(lower) alkyl wherein n is a positive integer less than 3.

2. A compound of the structural formula wherein n is a positive integer lessrthan 3.

3. A compound of the structuralformula 4. 17fi-methylsulfony1-4-androsten-3-one. 5. 17a-Inethylsulfonyl-4-androsten-3-one. 6. A compound of the structural formula 7. 17B-methylsulfiny1-4-androsten-3-one. 8. 17u-methylsulfinyl-4-androsten-3-one.

No references cited. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 